The epidermal growth factor receptor (EGFR) is overexpressed in the majority (approximately 90%) of head and neck squamous cell cancers (HNSC). EGFR inhibitors are attractive novel therapeutics to incorporate into current therapies as a strategy to achieve substantial improvement in the survival rates of patients with locally advanced HNSC. Binding the ligands to the EGFR activates a series of downstream signaling pathways, including the Ras/Erk/MAPK pathway and the P13K/Akt pathway. We have shown that the tyrosine kinase inhibitor 0SI-774 blocks EGFR signaling through the Ras/ErK/MAPK pathway but fails to inhibit the P13/Akt signaling pathway in selected patients with HNSC. We have shown that rapamycin and analog compunds, inhibitors in the P13/Akt downstream signaling pathway, reverse resistance to chemotherapy conferred by Akt hyperactivation in breast cancer cell lines. Clinical studies with 0SI-774 and other EGFR inhibitors show that not all patients respond to treatment. Thus, our central hypothesis is that EGFR blockade with 0SI-774 will inhibit the Ras/Erk/MAPK signaling pathway in the majority of HNSCs but that inhibition of the P13K/Akt pathway will require additional therapeutics. We will test this hypothesis by determining the molecular response of 0SI-774 in newly diagnosed patients with locally advanced HNSC enrolled in Phase I dose-finding trial of 0SI-774 combined with radiation therapy and cisplatin. Along with the tumor specimens, HNSC cell lines will be used in preclinical in vivo and in vitro experiments. The molecular findings from the patient tumor specimens will be used to validate our model system. Confirmation of the in vitro/in vivo model will allow us to explore the effects of adding other inhibitors of the P13K/Akt pathway in the model system. The Specific Aims are: (1) To determine the molecular response of 0SI-774 in newly diagnosed patients with locally advanced HNSC enrolled in a phase I trial. (2). To determine the biological effects of 0SI-774 on the EGFR signaling pathways in vitro and in vivo HNSC models. (3). To determine the molecular effects of combining 0SI-774 with inhibitors of the P13K/Akt signaling pathway in preclinical HNSC models. (4) To conduct a phase I clinical trial that incorporates inhibitors of P13k/Akt downstream targets to our backbone regimen of OSI-774/cisplatin/radiation treatment of patients with locally advanced head and neck cancer.